{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T04:47:15Z","timestamp":1785646035422,"version":"3.56.0"},"reference-count":122,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Key R&D Program of China","doi-asserted-by":"publisher","award":["2024YFA1210100"],"award-info":[{"award-number":["2024YFA1210100"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004829","name":"Science and Technology Department of Sichuan Province","doi-asserted-by":"publisher","award":["2026NSFSC0564"],"award-info":[{"award-number":["2026NSFSC0564"]}],"id":[{"id":"10.13039\/501100004829","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2026NSFSC0564"],"award-info":[{"award-number":["2026NSFSC0564"]}],"id":[{"id":"https:\/\/ror.org\/04323m874","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82304395"],"award-info":[{"award-number":["82304395"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82304395"],"award-info":[{"award-number":["82304395"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013365","name":"\u201cQimingxing\u201d Research Fund for Young Talents","doi-asserted-by":"publisher","award":["HXQMX0110"],"award-info":[{"award-number":["HXQMX0110"]}],"id":[{"id":"10.13039\/501100013365","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100032767","name":"Sichuan Medical Association","doi-asserted-by":"crossref","award":["2022TG01"],"award-info":[{"award-number":["2022TG01"]}],"id":[{"id":"10.13039\/100032767","id-type":"DOI","asserted-by":"crossref"}]},{"award":["2022TG01"],"award-info":[{"award-number":["2022TG01"]}],"id":[{"id":"https:\/\/ror.org\/00ft2kj97","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Bioengineering"],"abstract":"<jats:p>The clinical translation of nucleic acids is severely hindered by multiple delivery barriers, such as enzymatic degradation, poor cellular uptake, endosomal entrapment, and rapid systemic clearance. Despite the remarkable therapeutic potential of these agents, conventional delivery systems often fail to address these challenges. Lipid nanoparticles (LNPs) have emerged as a versatile platform to overcome these obstacles, offering tunable physicochemical properties, high encapsulation efficiency, and pH-responsive endosomal escape. This review summarizes recent advances in LNP-based respiratory and gastrointestinal mucosal delivery of nucleic acids, with emphasis on formulation strategies for overcoming mucus and epithelial barriers. To overcome mucosal barriers, LNP studies have shown that keeping particle size below the local mucus mesh size (~100 nm), tuning surface charge toward near-neutrality via pH-responsive ionizable lipids, and maintaining a neutral, deformable, moderately PEGylated surface during the mucin transport stage can increase transmucosal diffusivity several-fold over conventional cationic LNPs. We further discuss current limitations and propose future directions, emphasizing the need for the integration of the pathological and physiological characteristics of specific mucosa with artificial intelligence (AI) platforms to develop intelligent and personalized delivery platforms with \u201cspatiotemporal adaptive\u201d capabilities.<\/jats:p>","DOI":"10.3390\/bioengineering13080884","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T08:20:18Z","timestamp":1785486018000},"page":"884","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Recent Advances in Lipid Nanoparticle-Mediated Respiratory and Gastrointestinal Mucosal Delivery of Nucleic Acids"],"prefix":"10.3390","volume":"13","author":[{"given":"Zefan","family":"Liu","sequence":"first","affiliation":[{"name":"First People\u2018s Hospital of Shuangliu District (West China Airport Hospital of Sichuan University), Chengdu 610093, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Fu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug, West China School of Pharmacy, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Mo","sequence":"additional","affiliation":[{"name":"Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug, West China School of Pharmacy, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug, West China School of Pharmacy, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenao","family":"Yan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug, West China School of Pharmacy, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Hu","sequence":"additional","affiliation":[{"name":"First People\u2018s Hospital of Shuangliu District (West China Airport Hospital of Sichuan University), Chengdu 610093, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minglu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lian","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug, West China School of Pharmacy, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2496-7141","authenticated-orcid":false,"given":"Yucheng","family":"Xiang","sequence":"additional","affiliation":[{"name":"Sichuan Higher Education Institute Key Laboratory of Structure-Specific Small Molecule Drugs, Institute of Materia Medica, School of Pharmacy, Chengdu Medical College, Chengdu 610500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1038\/s41392-022-01298-z","article-title":"Nucleic Acid Drug Vectors for Diagnosis and Treatment of Brain Diseases","volume":"8","author":"Lu","year":"2023","journal-title":"Signal Transduct. 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